Showing papers by "Peter MacCallum Cancer Centre published in 2004"
Erasmus University Rotterdam1, Peter MacCallum Cancer Centre2, Institut Gustave Roussy3, Charité4, French Institute of Health and Medical Research5, Katholieke Universiteit Leuven6, Leiden University7, European Organisation for Research and Treatment of Cancer8, The Royal Marsden NHS Foundation Trust9
TL;DR: If response induction is the only aim of treatment, a daily dose of400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.
1,525 citations
TL;DR: This perspective article seeks to clarify which cells fall under the NKT-cell umbrella, and which might be best considered as separate.
Abstract: Recent years have seen so-called natural killer T (NKT) cells emerge as important regulators of the immune response. The existence of NKT-cell subsets, and other types of T cell that resemble NKT cells, is an ongoing source of confusion in the literature. This perspective article seeks to clarify which cells fall under the NKT-cell umbrella, and which might be best considered as separate.
1,134 citations
TL;DR: This study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.
Abstract: Phosphatidylinositol 3'-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.
911 citations
TL;DR: In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone, suggesting the vaccine is safe and highly potent immunologically.
Abstract: NY-ESO-1 is a “cancer-testis” antigen expressed in many cancers. ISCOMATRIX is a saponin-based adjuvant that induces antibody and T cell responses. We performed a placebo-controlled clinical trial evaluating the safety and immunogenicity of recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant. Forty-six evaluable patients with resected NY-ESO-1-positive tumors received three doses of vaccine intramuscularly at monthly intervals. The vaccine was well tolerated. We observed high-titer antibody responses, strong delayed-type hypersensitivity reactions, and circulating CD8+ and CD4+ T cells specific for a broad range of NY-ESO-1 epitopes, including known and previously unknown epitopes. In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone. The vaccine is safe and highly potent immunologically.
448 citations
TL;DR: It is demonstrated that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
Abstract: IL-21 is a recently identified cytokine that stimulates mouse NK cell effector functions in vitro. In this study we demonstrate that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function. IL-21 treatment results in increased cell size and granularity and a corresponding decrease in cell viability and proliferative potential. These cells up-regulate the expression of the inhibitory CD94-NKG2A receptor complex and the activation markers CD154 and killer cell, lectin-like-receptor G1. Surprisingly, IL-21 treatment also results in down-regulation of the pan-NK marker, NK1.1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-gamma production. In vivo treatment with IL-21 results in a very similar activation and phenotypic maturation of NK cells as well as a potent increase in NK cell-mediated anti-tumor immunity that is perforin dependent. These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
292 citations
TL;DR: HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.
Abstract: Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.
291 citations
TL;DR: These findings provide the first evidence that the exocyst functions as a Rab effector complex in mammalian cells.
280 citations
TL;DR: Recent knowledge about TRAIL and its receptors as promising targets for cancer therapy is summarized.
Abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. Preclinical studies in mice and non-human primates have shown the potential utility of recombinant soluble TRAIL and agonistic anti-DR5 or DR4 antibodies for cancer therapy. Moreover, we have recently revealed a vital role for endogenously expressed TRAIL in immunosurveillance of developing and metastatic tumors. In this review, we summarize recent knowledge about TRAIL and its receptors as promising targets for cancer therapy.
260 citations
TL;DR: The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.
Abstract: Aims To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. Methods This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. Results A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. Conclusions The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.
253 citations
TL;DR: A critical role for NK cells and γδTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition is reflected.
Abstract: Few studies have demonstrated that innate lymphocytes play a major role in preventing spontaneous tumor formation. We evaluated the development of spontaneous tumors in mice lacking beta-2 microglobulin (beta2m; and thus MHC class I, CD1d, and CD16) and/or perforin, since these tumor cells would be expected to activate innate effector cells. Approximately half the cohort of perforin gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked beta2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%). B cell lymphomas from perforin/beta2m gene-targeted mice effectively primed cell-mediated cytotoxicity and perforin, but not IFN-gamma, IL-12, or IL-18, was absolutely essential for tumor rejection. Activated NK1.1+ and gammadeltaTCR+ T cells were abundant at the tumor site, and transplanted tumors were strongly rejected by either, or both, of these cell types. Blockade of a number of different known costimulatory pathways failed to prevent tumor rejection. These results reflect a critical role for NK cells and gammadeltaTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition.
227 citations
TL;DR: It is concluded that stem and transient amplifying cells reside in this location, while differentiating (K15 negative) cells are found in the shallow rete ridges of adult skin in situ.
TL;DR: Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
Abstract: The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
TL;DR: It is demonstrated that immature DC are rapidly eliminated by NK cells in vivo via a pathway dependent on the TNF-related apoptosis-inducing ligand (TRAIL) which suggested that NK cell TRAIL might regulate responses to vaccination by controlling the survival of Ag-loaded DC.
Abstract: Recent studies have implicated a possible role for NK cells in regulating dendritic cells (DC) in vitro. In the present study, we demonstrate that immature DC are rapidly eliminated by NK cells in vivo via a pathway dependent on the TNF-related apoptosis-inducing ligand (TRAIL). Elimination of NK cells and/or neutralization of TRAIL function during immunization with immature DC loaded with nonself or tumor Ags significantly enhanced T cell responses to these Ags and Ag-specific tumor immunity. These data suggested that NK cell TRAIL might regulate responses to vaccination by controlling the survival of Ag-loaded DC.
TL;DR: Hypermethylation and silencing of specific SOCS genes in the ovary, and to a lesser extent in breast, may augment cytokine responsiveness in these tissues, thereby contributing to oncogenesis.
Abstract: Suppressor of cytokine signaling (SOCS) proteins have emerged as critical attenuators of cytokine-mediated processes, suggesting a role in the suppression of tumorigenesis. In the ovary and mammary gland, cytokines such as prolactin and IL-6 are important regulators of growth and differentiation. We have investigated whether silencing or inactivation of SOCS genes occurs in ovarian and breast carcinomas. The SOCS1 and SOCS2 CpG islands were found to be hypermethylated in 23 and 14% of primary ovarian cancers, respectively, whereas only SOCS1 was methylated in breast cancers (9%). Methylation of these genes did not occur in normal tissues. No correlation was apparent between methylation and loss of heterozygosity, and no somatic mutations were found in a large panel of carcinomas. Aberrant methylation of these SOCS genes correlated with transcriptional silencing in ovarian and breast cancer cell lines, since expression was induced by the demethylating agent 5-azadeoxycytidine. SOCS3 was not hypermethylated in either cancer type. Consistent with this data, SOCS1 and SOCS2 but not SOCS3 suppressed the growth of ovarian and breast cancer cells. Hypermethylation and silencing of specific SOCS genes in the ovary, and to a lesser extent in breast, may augment cytokine responsiveness in these tissues, thereby contributing to oncogenesis.
TL;DR: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.
Abstract: Purpose To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. Patients and Methods Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. Results A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P = .019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intens...
TL;DR: It is suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.
Abstract: Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.
TL;DR: It is shown that granulocytic cells deficient in the c‐MYC antagonist MAD1 display increased cell volume, rDNA transcription and protein synthesis, providing a mechanism for coordination of ribosome biogenesis and cell growth under conditions of sustained growth inhibition such as granulocyte differentiation.
Abstract: The regulation of cell mass (cell growth) is often tightly coupled to the cell division cycle (cell proliferation). Ribosome biogenesis and the control of rDNA transcription through RNA polymerase I are known to be critical determinants of cell growth. Here we show that granulocytic cells deficient in the c-MYC antagonist MAD1 display increased cell volume, rDNA transcription and protein synthesis. MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. Using siRNA, UBF was shown to be required for c-MYC-induced rDNA transcription. These data demonstrate that MAD1 and c-MYC reciprocally regulate rDNA transcription, providing a mechanism for coordination of ribosome biogenesis and cell growth under conditions of sustained growth inhibition such as granulocyte differentiation.
TL;DR: This screen demonstrates the utility of large-scale N-ethyl-N-nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.
Abstract: Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet production, we have executed a large-scale modifier screen with genetically thrombocytopenic Mpl-/- mice by using N-ethyl-N-nitrosourea mutagenesis. Here we show that mutations in the c-Myb gene cause a myeloproliferative syndrome and supraphysiological expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. This screen demonstrates the utility of large-scale N-ethyl-N-nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.
TL;DR: In this paper, a combination of IL-2 and IL-18 was shown to suppress tumor metastases via perforin-mediated cytotoxicity and FasL effector mechanism.
Abstract: Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D–NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor–related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.
TL;DR: Postradiotherapy inflammatory changes detected by FDG-PET are positively correlated with tumor response, suggesting that tumor radioresponsiveness and normal tissue radiosensitivity may be linked.
Abstract: Purpose To investigate the relationship between positron emission tomography (PET) detected inflammatory changes in irradiated normal tissues and metabolic response at tumor sites in patients receiving radical radiotherapy for non–small-cell lung cancer. The prognostic significance of these changes was also studied. Methods In 73 consecutive patients, 18F-fluorodeoxyglucose (FDG) PET was performed at a median of 70 days after completion of radical radiotherapy. Radiation-induced inflammatory change was scored for normal tissues within the radiation treatment volume using a 0–3 grading scale. Metabolic tumor response was assessed using a pattern-recognition algorithm comparing pre- and posttreatment scans. Prognostic significance of inflammatory changes was tested using the Cox proportional hazards regression model. Results Increased FDG uptake in normal tissues (radiotoxicity) was associated with a greater likelihood of complete or partial tumor response on both PET (p = 0.0044) and computed tomography (p = 0.029). Prognostic stratification provided by PET response was both significant and of a similar magnitude in patients with low- and high-grade radiotoxicity. Conclusion Postradiotherapy inflammatory changes detected by FDG-PET are positively correlated with tumor response, suggesting that tumor radioresponsiveness and normal tissue radiosensitivity may be linked. Prognostic stratification provided by PET is not compromised by inflammatory changes if a meticulous visual response assessment technique is used.
TL;DR: It is demonstrated that the ability to regenerate a fully stratified epidermis with appropriate spatial and temporal expression of differentiation markers in a short-term in vitro organotypic culture system is an intrinsic characteristic of both epidermal stem and transit-amplifying cells, although the stem cell fraction is most capable of achieving homeostasis.
Abstract: Given our recent discovery that it is possible to separate human epidermal stem cells of the skin from their more committed progeny (ie, transit-amplifying cells and early differentiating cells) using FACS techniques, we sought to determine the comparative tissue regeneration ability of these keratinocyte progenitors We demonstrate that the ability to regenerate a fully stratified epidermis with appropriate spatial and temporal expression of differentiation markers in a short-term in vitro organotypic culture system is an intrinsic characteristic of both epidermal stem and transit-amplifying cells, although the stem cell fraction is most capable of achieving homeostasis Early differentiating keratinocytes exhibited limited short-term tissue regeneration under specific experimental conditions in this assay, although significant improvement was obtained by manipulating microenvironmental factors, that is, coculture with minimally passaged dermal cells or exogenous supply of the ECM protein laminin-10/11 Importantly, transplantation of all classes of keratinocyte progenitors into an in vivo setting demonstrated that tissue regeneration can be elicited from stem, transit-amplifying, and early differentiating keratinocytes for up to 10 weeks These data illustrate that significant proliferative and tissue-regenerative capacity resides not only in keratinocyte stem cells as expected, but also in their more committed progeny, including early differentiating cells
TL;DR: An update is provided on the transcription-dependent and –independent events that may be important for the anti-tumor activities of HDACi and the use of these compounds in combination with other chemotherapeutic drugs.
Abstract: Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number of structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity of all eleven class I and II HDACs. While these agents demonstrate many features required for anti-cancer activity such as low toxicity against normal cells and an ability to inhibit tumor cell growth and survival at nanomolar concentrations, their mechanisms of action are largely unknown. Initially, a model was proposed whereby HDACi-mediated transactivation of a specific gene or set of genes was responsible for the inhibition of cell cycle progression or induction of apoptosis. Given that HDACs can regulate the activity of a number of nonhistone proteins and that histone acetylation is important for events such as DNA replication and mitosis that do not directly involve gene transcription, it appears that the initial mechanistic model for HDACi may have been too simple. Herein, we provide an update on the transcription-dependent and -independent events that may be important for the anti-tumor activities of HDACi and discuss the use of these compounds in combination with other chemotherapeutic drugs.
TL;DR: This study provides the first functional evidence that caveolin-1 regulates primary breast tumor growth and spontaneous metastasis of breast cancer.
Abstract: Caveolin-1 was identified in a screen for genes involved in breast cancer progression. Caveolin-1 is the major protein component of caveolae, flask-shaped invaginations found in a number of different cell types. Using an orthotopic model of spontaneous breast cancer metastasis, caveolin-1 was found to be expressed in low and non-metastatic primary tumors, but at much lower levels in highly metastatic 4T1.2 and 4T1.13 tumors. Exogenous expression of caveolin-1 at moderate levels in 4T1.2 cells was sufficient to suppress primary tumor growth after inoculation of cells into the mammary gland. Expression of high levels of caveolin-1 also inhibited subsequent metastasis to distant organs. Cells expressing high levels of caveolin-1 showed reduced capacity to invade Matrigel, diminished response to laminin-1 stimulation and decreased metastasis to lung and bone. This study provides the first functional evidence that caveolin-1 regulates primary breast tumor growth and spontaneous metastasis of breast cancer.
TL;DR: It is demonstrated that in the presence of perforin, the protease activity of granzyme M rapidly and effectively induces target cell death.
TL;DR: It is shown that Hsp72 blocks cytochrome c release from mitochondria in response to cytotoxic stress and that permeabilization of the outer mitochondrial membrane is the critical point in deciding the fate of the cell.
TL;DR: The dinuclear platinum complex trans-[[Pt(NH(3))(2)Cl](2)micro-dpzm](2+)(di-Pt) binds inside cucurbit[7]uril with slow exchange kinetics which does not significantly affect the cytotoxicity of the dinuclear complex but reactivity at the platinum centre is reduced.
TL;DR: A molecular marker-based map of perennial ryegrass (Lolium perenne L.) has been constructed through the use of polymorphisms associated with expressed sequence tags (ESTs), providing the basis for in silico comparative genetic mapping, as well as the evaluation of co-location between QTLs and functionally associated genetic loci.
Abstract: A molecular marker-based map of perennial ryegrass (Lolium perenne L.) has been constructed through the use of polymorphisms associated with expressed sequence tags (ESTs). A pair-cross between genotypes from a North African ecotype and the cultivar Aurora was used to generate a two-way pseudo-testcross population. A selection of 157 cDNAs assigned to eight different functional categories associated with agronomically important biological processes was used to detect polymorphic EST–RFLP loci in the F1(NA6 × AU6) population. A comprehensive set of EST–SSR markers was developed from the analysis of 14,767 unigenes, with 310 primer pairs showing efficient amplification and detecting 113 polymorphic loci. Two parental genetic maps were produced: the NA6 genetic map contains 88 EST–RFLP and 71 EST–SSR loci with a total map length of 963 cM, while the AU6 genetic map contains 67 EST–RFLP and 58 EST–SSR loci with a total map length of 757 cM. Bridging loci permitted the alignment of homologous chromosomes between the parental maps, and a sub-set of genomic DNA-derived SSRs was used to relate linkage groups to the perennial ryegrass reference map. Regions of segregation distortion were identified, in some instances in common with other perennial ryegrass maps. The EST-derived marker-based map provides the basis for in silico comparative genetic mapping, as well as the evaluation of co-location between QTLs and functionally associated genetic loci.
TL;DR: Sinonasal undifferentiated carcinoma is an uncommon malignancy associated with poor prognosis and the optimal treatment approach has not been established was performed.
Abstract: Background. Sinonasal undifferentiated carcino- ma (SNUC) is an uncommon malignancy associated with poor prognosis. The optimal treatment approach for SNUC has not been established was performed. Methods. A retrospective review of all patients with SNUC seenatthePeterMacCallumCancerCentreovera12-yearperiod. Results. Ten patients with SNUC were identified, with nine having locally advanced disease (T4). Seven were treated with three cycles of platinum and 5-fluorouracil followed by radiation with two cycles of concurrent platinum. In these seven patients, the 2-year progress on-free survival was 43% (95% CI, 11% to 82%) and the 2-year overall survival was 64% (95% CI, 23% to 91%). One patient with a T1N0 nasal cavity tumor treated with radiation alone has not had a relapse. Two patients who were treated with initial surgical resection, prior to referral to our institution, received postoperative radiation, but they subse- quently had relapses and died. Conclusion. Induction chemotherapy followed by concur- rent chemoradiation is a promising treatment strategy for SNUC. A 2004 Wiley Periodicals, Inc. Head Neck 26: 435-441, 2004
TL;DR: Position emission tomography scanning appears to accurately change the stage or appropriately alter the therapy of almost a third of patients with advanced primary rectal cancer, and is suggested to be considered part of standard workup for such patients, particularly if neoadjuvant preoperative therapy is being considered as part of primary management.
Abstract: Purpose: The influence of positron emission tomography in the management of recurrent rectal cancer is well established but its role in primary rectal cancer remains uncertain. This study therefore prospectively assesses the impact of position emission tomography scanning on the management of primary rectal cancer. Methods: Forty-six patients with advanced primary rectal cancer referred for consideration of adjuvant preoperative therapy underwent position emission tomography scanning. The referring physicians prospectively recorded each patient’s stage following conventional imaging and the proposed treatment plan prior to position emission tomography scanning. This was then compared with subsequent stage and actual management implemented, and the appropriateness of position emission tomography-induced changes was noted by subsequent clinical follow-up. Results: The surgical management of 36 of 46 patients (78 percent) was unchanged as a result of position emission tomography, even though position emission tomography upstaged disease in 3 of 36 cases (8 percent) and downstaged disease in 5 of 36 cases (14 percent). In 8 of 46 cases (17 percent), management was altered because of the position emission tomography scan findings, including 6 cases (13 percent) in which surgery was cancelled and 2 other cases (4 percent) in which the radiotherapy field was changed. Where available, follow-up confirmed the appropriateness of position emission tomography-induced management change in each case. Two patients had a change in therapy independent of the position emission tomography scan due to clinical circumstances. Overall tumor stage was changed following position emission tomography in 18 of 46 patients (39 percent). Conclusion: Position emission tomography scanning appears to accurately change the stage or appropriately alter the therapy of almost a third of patients with advanced primary rectal cancer. In view of this, we suggest that position emission tomography scanning be considered part of standard workup for such patients, particularly if neoadjuvant chemoradiation is being considered as part of primary management.
TL;DR: Two cases of adults undergoing treatment for hematological malignancies who developed RPLS are reported, and the importance of early recognition and institution of appropriate management in reducing the risk of development of permanent neurological disability is emphasized.
Abstract: Reversible posterior leukoencephalopathy syndrome (RPLS) is an uncommon but distinctive clinicoradiological entity comprising of headache, seizures, visual disturbance, and altered mental function, in association with posterior cerebral white matter edema. With appropriate management, RPLS is reversible in the majority of cases. Previous reported associations of RPLS include hypertension, eclampsia, renal failure, and use of immunosuppressive drugs; reports in the adult hematology setting are rare. We report two cases of adults undergoing treatment for hematological malignancies who developed RPLS, and we emphasize the importance of early recognition and institution of appropriate management in reducing the risk of development of permanent neurological disability.